Chronic pain is a large and expensive medical problem that according to the Institute of Medicine of the National Academies, afflicts greater than 100 million Americans; a rate 10X the number of cancer sufferers, 7X those with coronary heart disease and 4X the number of Americans with diabetes. The effects of pain contribute to annual costs to US society of $560-$635 billion attributable to health care, rehabilitation and lost worker productivity. Unresolved pain can result in longer hospital stays, increased rates of re-hospitalization, increased outpatient visits, and decreased ability to function which results in an inability to work and maintain health insurance. ?9?10 neuronal nicotinic-acetylcholine receptors (nAChRs) are a putative non-opioid target for the treatment of neuropathic pain states. Selective antagonism of ?9?10 nAChRs by ?-conotoxins produced by marine mollusks of the Conus genus show acute, cumulative and extended reversal of pain states in nerve constriction or ligation models. However these peptide drugs are difficult to translate into practical therapeutics and only a limited number of purposefully-designed small molecule antagonists for ?9?10 nAChRs have been described in the patent or scientific literature. We have discovered a clinically prescribed class of molecules that is a viable starting point for the discovery and development of proprietary high potency small molecule antagonists of the human ?9?10 nAChRs. The prototype molecules already have submicromolar potency at the target. The proposed grant objectives are to understand a) what substitutions define antagonist potency and selectivity at ?9?10 nAChRs; b) what is the metabolic stability of these antagonists and c) what levels of these molecules are required for in vivo efficacy in rodent models of post- surgical and neuropathic pain. The outcome of the proposed work will be a lead candidate antagonist of human ?9?10 nAChRs with receptor selectivity, metabolic stability and in vivo efficacy.